title: Determining pathogenicity of genetic variants in hypertrophic cardiomyopathy: importance of periodic reassessment.
abstract: OBJECTIVE
  Major advances have been made in our understanding and clinical application of genetic testing in hypertrophic cardiomyopathy. Determining pathogenicity of a single-nucleotide variant remains a major clinical challenge. This study sought to reassess single-nucleotide variant classification in hypertrophic cardiomyopathy probands.
  
  
  METHODS
  Consecutive probands with hypertrophic cardiomyopathy with a reported pathogenic mutation or variation of uncertain significance were included. Family and medical history were obtained. Each single-nucleotide variant was reassessed by a panel of four reviewers for pathogenicity based on established criteria together with updated cosegregation data and current population-based allele frequencies.
  
  
  RESULTS
  From 2000 to 2012, a total of 136 unrelated hypertrophic cardiomyopathy probands had genetic testing, of which 63 (46%) carried at least one pathogenic mutation. MYBPC3 (n = 34; 47%) and MYH7 (n = 23; 32%) gene variants together accounted for 79%. Five variants in six probands (10%) were reclassified: two variation of uncertain significance were upgraded to pathogenic, one variation of uncertain significance and one pathogenic variant were downgraded to benign, and one pathogenic variant (found in two families) was downgraded to variation of uncertain significance. None of the reclassifications had any adverse clinical consequences.
  
  
  CONCLUSIONS
  Given the rapid growth of genetic information available in both disease and normal populations, periodic reassessment of single-nucleotide variant data is essential in hypertrophic cardiomyopathy.
authors.affiliation: 1] Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, Australia [2] Sydney Medical School, University of Sydney, Sydney, Australia.
authors.forename: Jipin
authors.initials: J
authors.lastname: Das K
authors.affiliation: 1] Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, Australia [2] Sydney Medical School, University of Sydney, Sydney, Australia.
authors.forename: Jodie
authors.initials: J
authors.lastname: Ingles
authors.affiliation: 1] Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, Australia [2] Sydney Medical School, University of Sydney, Sydney, Australia.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Bagnall
authors.affiliation: 1] Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, Australia [2] Sydney Medical School, University of Sydney, Sydney, Australia [3] Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia.
authors.forename: Christopher
authors.initials: C
authors.lastname: Semsarian
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D024722:Cardiac Myosins / Q000235:genetics*; D002312:Cardiomyopathy, Hypertrophic / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005820:Genetic Testing; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D018995:Myosin Heavy Chains / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult; D000099163:Myosin Binding Protein C
chemical_list: D024722:Cardiac Myosins; D002352:Carrier Proteins; D018995:Myosin Heavy Chains; D000099163:Myosin Binding Protein C; C501641:MYH7 protein, human